Molecular Switch Turns on Brown Fat Manufacture

Action Points

Explain to interested patients that brown adipose tissue converts excess energy into heat instead of storing it as fat.

Note that this study suggests it may be possible to induce the manufacture of brown fat in the body, perhaps opening the door to novel treatments for obesity.

TORONTO, July 30 -- In a finding with possible implications for human obesity treatment, researchers have pinned down a molecular switch that causes the development of so-called brown adipose tissue.

In mice, precursor cells activated by the switch developed into fats of brown adipose tissue, which then turned excess glucose into heat, according to Bruce Spiegelman, PhD, of the Dana-Farber Cancer Institute in Boston, and colleagues.

The finding raises the possibility of modifying an obese patient's cells in the lab and then transplanting them to create brown fat that burns off excess energy, Dr. Spiegelman and colleagues wrote online in Nature.

Alternatively, they said, it may be possible to find natural or synthetic compounds with the same effect, which " could have great value in human metabolic disease."

When it's activated -- usually by cold -- brown adipose tissue initiates a series of pathways that convert free fatty acids and glucose into heat, rather than storing them.

In humans, brown fat is usually found in infants, who are unable to maintain body heat by shivering. The tissue had been thought to vanish long before adulthood, until three studies earlier this year showed it can still be present and active in later life. (See Brown Fat Present, Active In Adults)

Dr. Spiegelman and colleagues showed last year that a protein called PRDM16 is involved in the development of brown fat from precursor cells, but they suspected that at least one other protein was also needed.

In a series of in vitro experiments, they zeroed in on a protein called C/EBP-ÃŸ, which is expressed in brown fat cells. The two proteins bind together, they found, to form a complex that turns muscle precursor cells into brown fat.

In experiments using mice, the researchers found that knocking out the gene for either protein induced defects in the brown fat of embryonic animals, including lower levels of UCP1, a protein that plays a key role in turning excess energy into heat.

Interestingly, the two proteins together also have the ability to turn other types of cells into brown fat.

After six to eight days, mouse embryonic fibroblasts or primary skin fibroblasts expressing the two factors had differentiated into lipid-filled adipocytes, the researchers said.

A similar experiment using human skin fibroblasts had the same result, they said.

In a final series of experiments, the researchers transplanted engineered cells into mice, including cells with an inactive vector, with each of the proteins singly, and with the two-protein complex.

The cells expressing vector or either PRDM16 or C/EBP-ÃŸ alone did not form visible fat tissues, the researchers said, but in contrast, the cells expressing both proteins formed "very distinct fat pads."

Using positron emission tomography -- the same technique used to show brown fat is active some adults -- the researchers saw that the new fat pads functioned as a sink for active glucose disposal, just as native brown fat does.

The results "give a lot more credence" to the notion of manipulating brown fat as a potential treatment for obesity and diabetes, Dr. Spiegelman said in a statement.

One possible strategy, he said, would be to remove some tissue from the patient, add the switch, and return it to the patient to form brown fat.

But it may also be possible to mimic the effect with drugs. "If we can find a hormone that (increased the manufacture of brown fat)," he said, "it's reasonable to think that it might provide a direct antiobesity treatment."

The study had support from the NIH and the Picower Foundation. The researchers did not report any conflicts.

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